Lithium salts have a long history of human consumption beginning in the 1800s. In psychiatry, they have been used to treat mania and as a prophylactic for depression since the mid-20th century (Shorter 2009). Today, lithium salts are used as a mood stabilizer for the treatment of bipolar disorder and also, off-label, for other psychiatric indications. For example, lithium is the only drug that consistently reduces suicidality in patients with neuropsychiatric disorders (Thies-Flechtner, Muller-Oerlinghausen et al. 1996, Goodwin, Fireman et al. 2003). Despite these effective medicinal uses, current FDA approved lithium pharmaceutics (lithium carbonate and lithium citrate) are plagued with a narrow therapeutic window that requires regular blood monitoring of plasma lithium levels and blood chemistry by a clinician to mitigate adverse events. Because conventional lithium salts (carbonate and citrate) are eliminated relatively quickly, multiple administrations throughout the day are required to safely reach therapeutic plasma concentrations.
Fragile X Syndrome and Modeling in Mice—
Fragile X syndrome (IAS) is the most common cause of inherited mental retardation. It is mediated by a mutation of the first identified autism-related gene, known as fragile X mental retardation-1 (Fmr1), which encodes the fragile X mental retardation protein (FMRP), an RNA binding protein that regulates translation (1, 2). This functional loss typically occurs when there is an expansion of the CGG trinucleotide repeat in the 5′ untranslated region of the Fmr1 gene (3, 4). This expansion appears as a weak, or “fragile-like”, end on the X chromosome. Since FXS is an X-linked developmental disorder, its severity and incidence is higher in males than females, affecting ˜1 in 4,000 males and ˜1 in 7,000 females (5). Transmission of the affected. Fmr1 allele may occur to female offspring from an affected male and to both male and female offspring from affected females. Importantly, patients affected by FXS have many characteristics commonly associated with Autism Spectrum Disorders (ASDs), characterized by several physical, mental, and behavioral abnormalities, including sleep disturbances, inattentiveness, hyperactivity, impaired cognition, seizure susceptibility, developmental delays, communication impairments, and anxiety (2, 6-12).
Glycogen Synthase Kinase—
Recent studies have shown that Fmr1 KO mice express elevated levels of glycogen synthase kinase 3 (GSK3) activity. GSK3 is a serine/threonine kinase that exists in two isoforms, GSK3α and GSK3β. Regulation of GSK3 is primarily mediated by inhibitory serine-phosphorylation, specifically at Ser21 of GSK3α and Ser9 of GSK3β. The inhibitory serine-phosphorylation of GSK3 is induced by a wide variety of signaling pathways that converge on GSK3, including protein kinase A (PKA), PKB (Akt), PKC, and ribosomal S6 kinase (13). Impairments in these inhibitory pathways can lead to hyperactive GSK3, which can contribute to a number of diseases including FXS, Alzheimer's disease, diabetes and mood disorders (14-16). In addition, to be fully activated, the GSK3 isoforms must be phosphorylated at the stimulatory phosphorylation sites, specifically at Tyr279 for GSK3α and Tyr216 for GSK3β. Studies of the actions of GSK3 were accelerated by the discovery that lithium, the classical treatment for bipolar disorder, is a selective inhibitor of this kinase (17). Lithium both directly inhibits GSK3 activity and also increases the inhibitory serine-phosphorylation of this enzyme (14).
Direct evidence that GSK3 may be involved in the pathology of FXS and thus a therapeutic target is currently an important area of investigation. Preliminary evidence for this connection was obtained in studies of the regulation of GSK3 in brain regions from Find. KO mice. Adult Fmr1 KO mice have lower levels of inhibitory GSK3α (Ser21) and GSK3β (Ser9) phosphorylation in several brain regions compared to wild-type littermates (18-23,46). The impaired serine-phosphorylation of GSK3 in adult Fmr1 KO mice was corrected by acute or chronic treatment with lithium (18-24). In addition, dfmr1 mutant Drosophila and Fmr1 KO mice display FXS behavioral phenotypes, including hyperactivity, social and cognitive impairment, all of which is reversed by lithium (18, 21, 23, 46, 47). Several selective inhibitors of GSK3, including SB-216763, TDZD-8 and VP0.7, also reverse these behavioral deficits (18, 46), confirming that this effect of lithium is mediated by inhibition of GSK3. Most importantly, lithium has been commonly used to treat mood instability and aggression in FXS patients (7). In a recent pilot clinical trial, FXS patients treated with lithium orally for 2 months showed improvements in aggression, anxiety, mood swings, tantrums, and abnormal outbursts (25; reviewed in 15 and 45). Positive responses were observed across the age range of the study cohort, suggesting that both children and young adults with FXS can benefit from this treatment. Taken together, these results support the hypothesis that impaired inhibition of GSK3 contributes to impairments in FXS and that lithium may have therapeutic potential by increasing the inhibitory phosphorylation of this enzyme.
Dendritic Abnormalities, BDNF and Lithium—
In addition to excessive GSK3 activity and behavioral impairment, Fmr1 KO mice and patients with FXS have impairments in neuronal spine density and morphology, manifested as abnormally long, thin spines in apical dendrites of neocortical and hippocampal pyramidal neurons (26). This suggests that dendritic spines fail to fully mature in this condition. Fmr1 KO mice also exhibit impairment in hippocampal long term potentiation, indicative of impaired synaptic plasticity, which can be fully restored with administration of brain derived neurotrophic factor (BDNF; 28, 46), a potent modulator of learning and memory, synaptic plasticity and neurogenesis (27). Moreover, lithium has been reported to increase BDNF levels in cortical neurons, which can be mimicked by pharmacological inhibition of GSK (29). Although lithium has therapeutic potential for the treatment of FXS, the lithium salt formulations currently available provide a narrow therapeutic window due, in part, to their poor physicochemical properties (30, 31). In addition, lithium has numerous side-effects and the optimal effective dose of lithium for the treatment of neurodegenerative disorders without eliciting side effects is currently unknown.